1q21.3

Various cancers

A survey of ECM1 expression in different tumors indicated that ECM1, although not tumor specific, is significantly elevated in many malignant epithelial tumors that gave rise to metastases (Wang et al., 2003). ECM1 overexpression has been described in cancers of the breast, thyroid (Lal et al., 2008; Kebebew et al., 2005; Pauws et al., 2004) and head and neck squamous cell carcinomas (HNSCC), specifically, laryngeal carcinomas. Other carcinomas with increased ECM1 expression include hepatocellular carcinoma, cholangiocarcinomas, cutaneous melanoma cell lines (Lal et al., 2013) and gastric carcinomas (Wu et al., 2014).
In addition, ECM1 upregulation has been associated with poor prognosis and metastases in breast (Lal et al., 2009), laryngeal (Gu et al., 2013; Han et al., 2006), hepatocellular (Chen et al., 2011), gastric and cholangiocarcinomas (Xiong et al., 2012). ECM1 expression also appears to be a predictor of primary uveal melanoma metastasis in a study using microarray expression (Onken et al., 2010).
Together with the observation that human recombinant ECM1 stimulates proliferation of cultured endothelial cells and promotes blood vessel formation in the chorioallantoic membrane of chicken embryos suggest that ECM1 is a possible trigger for angiogenesis, tumor progression and malignancies (Han et al., 2001). ECM1 has been correlated with elevated lymphatic and microvessel density in laryngeal (Han et al., 2006) and gastric tumors (Wu et al., 2014) and also correlated with estrogen responsiveness in breast cancer. In the latter ECM1 expression also correlates with VEGF-C suggesting that they may have a synergistic effect on lymphangiogenesis and facilitation of lymphatic metastases (Wu et al., 2012). In cholangiocarcinomas, ECM1 expression is also correlated with expression the tumor marker CA19-9, MMP-9 and the estrogen receptor (Xiong et al., 2012).
ECM1 also appears to play a role in the migration, invasion and attachment properties of cancer cells, as seen in studies of cholangiocarcinoma and melanoma cell lines (Xiong et al., 2012; Lal et al., 2013).
Overexpression of ECM1 in cancer cells appears to be mediated by the Akt/NF-κB signaling axis (Xiong et al., 2012). ECM1 expression is also partly regulated by transcription factor AP2C (TFAP2C) in melanoma cells, and its effect is mediated by direct interaction with the ECM1 promoter (Lal et al., 2013).

Lipoid proteinosis

Lipoid proteinosis, also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease.
Lipoid proteinosis is a rare autosomal recessive genodermatosis characterized by the deposition of an amorphous hyaline material in the skin, mucosa, and viscera. Papular infiltration of the margin of the lids producing itchy eyes, and infiltration in the tongue and its frenulum, in the larynx leading to hoarseness, and in the skin (e.g., elbows and axilla) are characteristic (Hamada et al., 2003; Hamada et al., 2002).

Lichen sclerosus et atrophicus

Lichen sclerosus (LS) is a chronic inflammatory skin disorder of unknown etiology that results in white plaques with epidermal atrophy. It has both genital and extragenital presentations. HLA-subtype susceptibility and high rates of other autoimmune disorders suggest that autoantibodies to specific mucocutaneous antigens may be involved in the etiology of lichen sclerosus. The similarities with lipoid proteinosis, which results from mutations in the ECM1 gene, suggested that this protein may be an autoantigen in lichen sclerosus. Indeed, circulating auto-antibodies to ECM1 were found in the sera of 67% of lichen sclerosus patients (Oyama et al., 2003; Oyama et al., 2004).
In conclusion lipoid proteinosis and lichen sclerosus are immunogenetic counterparts targeting ECM1.

Ulcerative colitis

A nonsynonymous SNP (rs11205387) has been associated with ulcerative colitis (Fisher et al., 2008). ECM1 variation was not associated with Crohns disease (Anderson et al., 2009). Incorporation of the analysis of ECM1 genetic variants into a diagnostic algorithm including serological and inflammatory markers resulted in improved accuracy in identifying inflammatory bowel disease and in particular, differentiating between ulcerative colitis and Crohns disease (Plevy et al., 2013).